Kaposi's sarcoma (KS) is a multifocal neoplasm that frequently complicates the clinical course of HIV-I positive individuals. As AIDS patients are living longer due to better treatment with reduction of their HIV-1 viral load, secondary tumor such as KS and non-Hodgkins lymphomas are becoming more common and problematic for clinicians. A significant problem in combating KS has been lack of identification of a clear-cut etiological agent, as well as absence of an animal model that contains all of the relevant human cellular constituents of KS lesions. Indeed, KS is a complex neoplasm that features participation of several different cell types including proliferating spindle-shaped tumor cells, endothelial cells, and dermal dendritic cells. Recently a novel DNA virus has been suggested as a plausible etiological agent (i.e. human herpesvirus-8; HHV-8), and a SCID-human skin grafting procedure developed. In this proposal, these advances are combined to determine if HHV-8 can cause cutaneous KS lesions in this novel animal model system. Once HHV-8 is introduced into engrafted full-thickness human skin, specific cell types that become infected and support viral DNA and RNA production will be identified using highly sensitive and specific localization techniques. In addition, the role of cytokines in HHV-8 induced KS will be examined with specific emphasis on induction of angiogenesis and expansile tumor formation. The range of potential mesenchymal cell targets in-vivo and in-vitro for HHV-8 will be determined, the influence of immunomodulatory agents on the multi-step process of KS lesion formation will be examined. To address the void in effective treatment modalities for KS, particularly in the setting of AIDS, this animal model system will be used to test the efficacy of anti-herpes agents at either preventing or reversing KS lesions. By successfully completing all 4 aims over the next 4 years, a better understanding of the etiology and pathophysiology of this common, enigmatic, and potentially deadly neoplasm will be had